Investigating novel routes to high intratumoural immunity

McMurray, Jack Luke ORCID: 0000-0003-0229-8560 (2022). Investigating novel routes to high intratumoural immunity. University of Birmingham. Ph.D.

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Abstract

Immune checkpoint blockade (ICB) has revolutionised treatment for high-mutation burden cancers that have deficient mismatch repair systems, and typically exhibit strong intratumoural immunity. However, extending this success to low-mutation burden settings that dominate many cancers remains a major challenge. For unknown reasons, low mutational cancer cohorts exhibit substantial heterogeneity in both the strength of intratumoural immunity, and in clinical prognosis. Colorectal cancer (CRC) represents a robust model to investigate such phenomena, since it comprises distinct subgroups that are ICB-responsive (microsatellite instability-high, MSI-H) and non-responsive (microsatellite stable, MSS) which exhibit high and low mutational burden, respectively. Utilising a TH1-centric signature, I demonstrate that MSS patients have a highly variable intratumoural immunity and that MHC Class II expression can stratify a high-immunity MSS subgroup (MSS-hi-CIRC). Subsequently, using multispectral immunofluorescence, I demonstrate that MSS-hi-CIRC patients have an immune infiltrate comparable to ICB-responsive CRC patients (MSI-H), despite substantially lower mutational loads and no specific genetic determinants. Finally, I demonstrate differences in the microenvironmental immunobiology of MSS-hi-CIRC and MSI-H patients that indicate distinct routes to establishing high intratumoural immunity and suggest MSS-hi-CIRC immunobiology results from microbiome-driven adjuntivisation of intratumoural immunity. Furthermore, by mining data from other low-mutation burden cancers, I demonstrate that MSS-hi-CIRC immunobiology defined here might occur across several cancer types. My results therefore indicate that MHC-II level stratifies patients with immunobiology like that of MSI-H patients, albeit arising from distinct mechanisms. The analyses and mechanistic model proposed have implications for both the understanding of differential clinical prognosis in MSS cancer patients, and for the development of new immunotherapies and microbiome-based therapies focussed on this grouping.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):